Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells.

Chia-Lung Tsai,Hsin-Shih Wang,Chi-Neu Tsai,Chiao-Yun Lin,Chyong-Huey Lai,Shih-Che Sue,Shun-Hua Chen,Angel Chao,Shih-Ming Jung,Tzu-Hao Wang

doi:10.18632/oncotarget.10500

Chia-Lung Tsai, Hsin-Shih Wang + Show 8 more

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https://doi.org/10.18632/oncotarget.10500

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Abstract

Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.

Highlights

Stress-induced phosphoprotein 1 (STIP1; Gene ID:10963) − a 62.6-kDa protein known as heat shock protein (HSP)-organizing protein [1] – was initially identified in yeast [2]
The results of our study indicate that HSP90 and its co-chaperone stress-induced phosphoprotein 1 (STIP1) are important regulators of the JAK2STAT3 pathway
We show for the first time that the N-terminus of STIP1 interacts with the N-terminus of Janus kinase 2 (JAK2) (Figure 2)

Summary

Introduction

Stress-induced phosphoprotein 1 (STIP1; Gene ID:10963) − a 62.6-kDa protein known as heat shock protein (HSP)-organizing protein [1] – was initially identified in yeast [2]. The TPR1 and TPR2B domains interact with HSP70, whereas the TPR2A and TPR2B domains are involved in the binding of STIP1 to HSP90 [4,5,6]. STIP1 functions as an adapter that directs HSP90 to HSP70-client protein complexes in the cytoplasm, modulating their chaperone activity [1]. These complexes are involved in a number of different cellular activities, including RNA splicing, transcription, protein folding, signal transduction, and cell cycle regulation [8, 9]. Studies in mice have shown that complete STIP1 loss-of-function causes embryonic lethality, increased caspase 3 activation, impaired cell proliferation and reduced expression of several HSP90 client proteins [10]. Mutational analyses revealed that the DP2 domain is critical when the glucocorticoid receptor is activated [5]

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